Leishmaniasis remains a serious problem in public health in many areas of the world. Understanding Leishmania transmission by sand flies involves the comprehension of how substances present in phlebotomine saliva can influence initial host anti-Leishmania immune response, and how the human immune response directed to salivary products may block such effects. Infection and disease progression in leishmaniasis are dependent on the initial host response to Leishmania. Our hypothesis is that sand fly salivary products influence the initial host response to Leishmania, and additionally that host response against phlebotomine saliva components, which may be mounted against uninfected bites, alters the course of infection. In order to explore such aspects we propose to: a) evaluate the effects of salivary products in the sensitization of human lymphocytes against Leishmania and b) follow and characterize human immune response against phlebotomine saliva upon natural and experimental exposure. We will take advantage of the system of in vitro sensitization of human lymphocytes against Leishmania to evaluate the effects of phlebotomine saliva antigen presentation and we will also address how the saliva products affect human dendritic cell maturation. On the other hand, for evaluating the human response against sand fly saliva, we will follow a cohort of children in the endemic area to determine the influence of human anti-saliva immune response on the development of leishmania infection and visceral leishmaniasis development. Following selection of responsive individuals, we will characterize in depth their humoral (IgG subclasses and specific recognition of selected antigens by immunoblotting). Following on the issue of antigenicity of individual molecules present in saliva, we will expose normal human volunteers to laboratory-reared Lutzomyia longipalpis bites, and determine on a time-course basis their recognition of specific bands. This proposal will uniquely start the bridge between murine/laboratory studies on the effect of sand fly saliva on leishmaniasis transmission to that of human/field work on the same subject, ultimately creating the groundwork for developing a insect-antigen derived vaccine against human leishmaniasis.